Associate Physician
Brigham and Women's Hospital

hilde-kari.guttormsen@channing.harvard.edu

Group B Streptococcus (GBS) is a major cause of neonatal infections in humans and is usually acquired by perinatal transmission from the genital tract of the mother to her child. Virtually all strains of GBS isolated from ill infants are encapsulated by one of the organisms' nine identified capsular polysaccharides. Studies from this laboratory have shown that type-specific antibodies of the IgG isotype in the mother, the only isotype that can cross the placenta, protect her infant from invasive disease. Unfortunately T-cell indpenedent antigens like polysaccharides are poor immunogens and do not induce immunologic memory. Clinical studies from this laboratory have shown that the response rate to the unconjugated type III polysaccharide in previously naive adults is approximately 50-60%. However, conjugation of type III polysaccharide to tetanus toxoid increased the response rate to greater than 90% in women of childbearing age and significantly enhanced the level of antibody achieved in most vaccines, indicating the recruitment of T-cell help and induction of polysaccharide-specific memory.

We have developed enzyme-linked immunosorbent assays (ELISAs) for detection of type-specific antibodies (GBS types Ia, Ib, II, III, and V) of all major immunoglobulin isotypes. These new assays are now used to evaluate the immune responses induced by new GBS conjugate vaccine cadidates in clinical trials and have allowed us to perform detailed studies of the humoral responses to these vaccines.

Studies from this laboratory using a murine type adoptive lymphocyte transfer model have demonstrated that adoptive transfer of splenocytes from mice immunized with the GBSIII-TT conjugate vaccine conferred anti-polysaccharide immunologic memory to naive recipient mice in dose-dependent manner. We are currently using this model to: 1) evaluate conjugate vaccines with different physicochemical properties for their ability to induce immunologic memory, and 2) to study the cellular interactions required for an immune response to these molecules.

A further goal for this work is to study the initial molecular and immunologic events that led to T cell recruitment by the glycoconjugate vaccines. We are using mice deficient in costimulatory ligand/receptor pairs (by targeted gene disruption by homologous recombination) or mice immunologically deprived of these receptor-ligand intercellular interactions to define the role for costimulatory molecules in the immune response to glycoconjugates. A further goal of this work is to investigate what are the important physio-chemical parameters of vaccine design that regulate T-cell help and induction of immunological memory.

Halstensen A, Lehmann AK, Guttormsen HK, Vollset SE, Bjune G, Naess A. Serum opsonins to serogroup B meningococci after disease and vaccination. NIPH Annals 1991;14:157-167. [abstract]

Guttormsen HK, Bjerknes R, Naess A, Lehmann V, Halstensen A, Soernes S, Solberg CO. Cross-reacting serum opsonins in patients with meningococcal disease. Infect Immun 1992;60:2777-2783. [abstract]

Guttormsen HK, Bjerknes R, Halstensen A, Naess A, Hoeiby EA, Solberg CO. Cross-reacting serum opsonins to meningococci after vaccination. J Infect Dis 1993;167:1314-1319. [abstract]

Guttormsen HK, Wetzler LM, Naess A. Humoral immune response to the class 3 outer membrane protein during the course of meningococcal disease. Infect Immun 1993;61:4734-4742. [abstract]

Guttormsen HK, Wetzler LM, Solberg CO. Humoral immune response to class 1 outer membrane protein during the course of meningococcal disease. Infect Immun 1994;62:1437-1443. [abstract]

Bjerknes R, Guttormsen HK, Solberg CO, Wetzler LM. Neisserial porins inhibit neutrophil actin polymerization, degranulation, opsonin receptor expression, and phagocytosis but prime the neutrophils to increase their oxidative burst. Infect Immun 1995;63:160-7. [abstract]

Guttormsen HK, Baker CJ, Edwards MS, Paoletti LC, Kasper DL. Quantitative determination of antibodies type III group B streptococcal polysaccharide. J Infect Dis 1996;173:142-50. [abstract]

Kasper DL, Paoletti LC, Wessels MR, Guttormsen HK, Carey VJ, Jennings HJ, Baker CJ. Immune response to type III group B streptococcal polysaccharide-tetanus toxoid conjugate vaccine. J Clin Invest 1996;98:2308-14. [abstract]

Guttormsen HK, Wetzler LM, Finberg RW, Kasper DL. Immunologic memory induced by a glycoconjugate vaccine in a murine adoptive lymphocyte transfer model. Infect Immun 1998;66:2026-2032. [abstract]

Wessels MR, Paoletti LC, Guttormsen HK, Michon F, D'Ambra AJ, Kasper DL. Structural properties of group B streptococcal type III polysaccharide conjugate vaccines that influence immunogenicity and efficacy. Infect Immun 1998;66:2186-2192. [abstract]

Baker CJ, Paoletti LC, Wessels MR, Guttormsen HK, Rench MA, Hickman ME, Kasper DL. Safety and Immunogenicity of Capsular Polysaccharide-Tetanus Toxoid Conjugate Vaccines for Group B Streptococcal Types Ia and Ib. J Infect Dis 1999;179:142-50. [abstract]

Lehmann AK, Halstensen A, Aaberge I, Holst J, Michaelsen TE, Sørnes S, Wetzler LM, Guttormsen HK. Human Opsonins Induced during Meningococcal Disease Recognize Outer Membrane Proteins PorA and PorB. Infect Immun. 1999;67:2552-60. [abstract]

Guttormsen HK, Sharpe AH, Chandraker AK, Brigtsen AK, Sayegh MH, Kasper DL. Cognate Stimulatory B-/T-Cell Interactions Are Critical for T-cell Help Recruited by Glycoconjugate Vaccines. Infect Immun. 1999;67:6375-84. [abstract]

Ram S, Mackinnon FG, Gulati S, McQuillen DP, Vogel U, Frosch M, Elkins C, Guttormsen HK, Wetzler LM, Oppermann M, Pangburn MK, Rice PA. The contrasting mechanisms of serum resistance of Neisseria gonorrhoeae and group B Neisseria meningitidis. Molecular Immunology. 1999;36:915-928. [abstract]

Wedege E, Bolstad K, Wetzler LM, and Guttormsen HK. IgG antibody levels to meningococcal porins in patient sera: Comparison of immunblotting and ELISA methods. IgG antibody levels to meningococcal porins in patient sera: comparison of immunoblotting and ELISA measurements. J Immunol Methods. 2000 Oct 20;244(1-2):9-15. [abstract]

Baker CJ, Paoletti LC, Rench MA, Guttormsen HK, Carey VJ, Hickman ME, Kasper DL. Use of capsular polysaccharide-tetanus toxoid conjugate vaccine for type II group B Streptococcus in healthy women. J Infect Dis. 2000 Oct;182(4):1129-38. Epub 2000 Sep 8. [abstract]